Abstract
The central nervous system (CNS) pharmacokinetics of the H1 receptor antagonist diphenhydramine (DPHM) were studied in 100- and 120-day-old fetuses, 10- and 30-day-old newborn lambs, and adult sheep using in vivo microdialysis. DPHM was administered i.v. at five infusion rates, with each step lasting 7 h. In all ages, cerebrospinal fluid (CSF) and extracellular fluid (ECF) concentrations were very similar to each other, which suggests that DPHM between these two compartments is transferred by passive diffusion. In addition, the brain-to-plasma concentration ratios were ≥3 in all age groups, suggesting the existence of a transport process for DPHM into the brain. Both brain and plasma DPHM concentrations increased in a linear fashion over the dose range studied. However, the ECF/unbound plasma and CSF/unbound plasma DPHM concentration ratios were significantly higher in the fetus and lambs (∼5 to 6) than in the adult (∼3). The factors fCSF and fECF, the ratios of DPHM areas under the curves (AUCs) in CSF and ECF to the plasma DPHM AUC, respectively, decreased with age, indicating that DPHM is more efficiently removed from the brain with increasing age. The extent of plasma protein binding of the drug increased with age. This study provides evidence for a transporter-mediated mechanism for the influx of DPHM into the brain and also for an efflux transporter for the drug, whose activity increases with age. Moreover, the higher brain DPHM levels in the fetus and lamb compared with the adult may explain the greater CNS effects of the drug at these ages.
Footnotes
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Financial support for this work was provided by the Canadian Institute of Health Research (CIHR). S.C.S.A.-Y. is a recipient of a CIHR Doctoral Fellowship. The current project is a part of S.C.S.A.-Y.'s Ph.D. thesis at University of British Columbia.
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Part of this work was previously presented as a poster in the 2002 ISSX meeting; 2002 Oct 27–31; Orlando, FL: Au-Yeung SCS, Gruber N, Riggs KW, and Rurak D (2002) Investigation of the CNS pharmacokinetics of diphenhydramine (DPHM) in sheep using microdialysis (Abstract). Drug Metab Rev34:134.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.013995.
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ABBREVIATIONS: CNS, central nervous system; BBB, blood brain barrier; DPHM, diphenhydramine; ECF, extracellular fluid; CSF, cerebrospinal fluid; MD, microdialysis; FEP, fluorinated ethylene propylene; AUC, area under the curve; ANOVA, analysis of variance; CLT, total body clearance; Vdss, steady-state volume of distribution.
- Received November 22, 2006.
- Accepted May 3, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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